Blood plasma is an easily accessible source of proteins which have diagnostic value, as it is in contact with practically all tissues in the human body. Plasma proteome contains not only proteins which function in or via plasma, e.g. albumin, immunoglobulins and cytokines, but also proteins which leak from tissues.1 During tumor growth, damage of normal or tumor tissues leads to release of cellular proteins into plasma. Currently, 196 proteins have been identified in human plasma, but up to 1175 distinct gene products may be present in human plasma.2 
Plasma has been extensively explored in searches for markers of tumorigenesis. However, attempts to find a single reliable early marker of human breast or ovarian cancer have not been fully successful. Variability of molecular mechanisms governing tumor growth and its spreading in the body indicates that an expression pattern of a few markers may be more informative than a single marker.3,9,16 This prompts a search for proteins which change their expression in an accessible diagnostic material, e.g. blood. Two-dimensional gel electrophoresis (2D-GE), liquid chromatography and mass spectrometry, as well as various array techniques have been used.3 Among described markers, CA125, CA15-3, CEA, and RS/DJ1 proteins have been proposed as useful markers to monitor breast cancer.3,4 CA125, apolipoprotein A1, transthyretin, inter-α trypsin inhibitor heavy chain H4, haptoglobin-1 and kallikrein have been proposed as markers of ovarian cancer.5-8 None of the identified protein markers has been found to predict cancer appearance and development with a probability value close to 100%. This can be explained by the presence of these proteins in normal nontransformed cells, as well as in tumor cells; in tumors, marker proteins change their activities or relocalize in cells.
A combination of a few markers was proposed to predict the appearance and development of tumors with higher accuracy, as compared to use of a single marker. The application of surface-enhanced laser desorption/ionization mass spectrometry (SELDI) provides one means of implementing such a multiparameter approach.9 A combination of identified markers would be the most preferable solution for such multiparameter diagnostics. However, SELDI does not provide identities of proteins or peptides in identified mass peaks.
Cytoplasmic serine hydroxymethyl transferase (cSHMT) is one of the key enzymes of one-carbon metabolism, the pathway which is altered in colorectal cancer.14 Increased expression of cSHMT has been found in metastatic human breast carcinoma cells MDA-MB-435, as compared to nonmetastatic cells.17 Whether cSHMT function is affected in breast and ovarian cancers remains to be investigated. T-box transcription factor 3 (Tbx3), on the contrary, is involved in development of mammary gland; mutations or lack of Tbx3 result in mammary hypoplasia, and even in lack of mammary glands.15 Tbx3 has been described as a potent inhibitor of senescence of neuronal cells and embryonal fibroblasts.18 Utrophin has been described first as a protein involved in development of neuromuscular junctions. However, utrophin detection in a variety of cells has indicated its role in organization of connections between cytoskeleton and transmembrane proteins. Utrophin has a number of splicing forms, and a variety of short isoforms have been described.13 Utrophin has been detected in mammary ductal epithelium and in stroma.19 Expressions of utrophin and its binding partner dystroglycan were found to be reduced in breast adenocarcinomas.19 It is possible that the decrease of utrophin in cells is accompanied by release of this protein into the plasma. cSHMT, Tbx3 and utrophin are known to function inside of cells, and their appearance in plasma in truncated forms suggests that they were released from cells and subjected to a limited proteolysis.
Herein is described the increased appearance of truncated forms of cSHMT, Tbx3 and utrophin in plasma of patients with breast and ovarian cancer. The use of these markers alone or, in a multiparameter approach, in combination with each other or in combination with other markers provides a significant development and improvement in cancer diagnostics.